Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing
Abstract Congenital neutropenia (CN) comprises a heterogeneous group of rare genetic disorders. While some CN cases present only with neutropenia, others present with additional extra‐hematological manifestations. The most common cause of CN is variants in ELANE; however, approximately 30 other gene...
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2025-06-01
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| Online Access: | https://doi.org/10.1002/hem3.70150 |
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| author | Séverine Marti Philippe Pellet Blandine Beaupain Léa Durix Julien Buratti Yves Réguerre Nathalie Aladjidi Saba Azarnoush Severine Clauin Wahid Abou Chahla Gilles Blaison Jeremy Bertand Damien Bodet Benoit Brethon Jessica Chane‐Teng Manon Delafoy Chrystelle Dupraz Virginie Gandemer Philippe Denizeau Alice Goldenberg Pierre Hirsch Anaïs l'Haridon Aude Marie‐Cardine Gabriella Vera Brigitte Nelken Laure Nizery Marie Nolla Marlène Pasquet Jérémie Rosain Louis Terriou Isabelle Plo Jean Donadieu Christine Bellanné‐Chantelot |
| author_facet | Séverine Marti Philippe Pellet Blandine Beaupain Léa Durix Julien Buratti Yves Réguerre Nathalie Aladjidi Saba Azarnoush Severine Clauin Wahid Abou Chahla Gilles Blaison Jeremy Bertand Damien Bodet Benoit Brethon Jessica Chane‐Teng Manon Delafoy Chrystelle Dupraz Virginie Gandemer Philippe Denizeau Alice Goldenberg Pierre Hirsch Anaïs l'Haridon Aude Marie‐Cardine Gabriella Vera Brigitte Nelken Laure Nizery Marie Nolla Marlène Pasquet Jérémie Rosain Louis Terriou Isabelle Plo Jean Donadieu Christine Bellanné‐Chantelot |
| author_sort | Séverine Marti |
| collection | DOAJ |
| description | Abstract Congenital neutropenia (CN) comprises a heterogeneous group of rare genetic disorders. While some CN cases present only with neutropenia, others present with additional extra‐hematological manifestations. The most common cause of CN is variants in ELANE; however, approximately 30 other genes have been implicated. Despite this, the genetic basis remains unknown in roughly 30% of cases. The clinical and genetic heterogeneity of CN makes diagnosis particularly challenging. To address this, we conducted exome or genome sequencing of 60 patients with a suspected diagnosis of CN that remained unresolved following targeted sequencing. A genetic diagnosis was established in 25 patients (42%). Variants were identified in 15 different genes. Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (GINS4, CARD11, ADA2, GINS1, LCP1, SASH3, and WAS). One‐third of the cases carried variants in genes linked to syndromic disorders (VPS13B, TAFAZZIN, CLPB, and TONSL), demonstrating variable penetrance of extra‐hematological phenotypes. A smaller subset (15%) harbored variants in genes associated with inherited bone marrow failure syndromes (BLM, RPL18, SAMD9, and SRP72), identified incidentally due to atypical presentations. Compared to patients with ELANE‐CN, these individuals were diagnosed later, had fewer severe bacterial infections and gingivitis, exhibited less profound neutropenia, lacked monocytosis, and had a granulocytic maturation arrest, often beyond the promyelocytic stage. A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells. This study highlights the significant contribution of exome and genome sequencing in diagnosing CN, given the phenotypic overlap, genetic heterogeneity, and variable penetrance of immunological and extra‐hematological features. |
| format | Article |
| id | doaj-art-a43e614f504c4aa7b8fde56df04af6fa |
| institution | OA Journals |
| issn | 2572-9241 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
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| series | HemaSphere |
| spelling | doaj-art-a43e614f504c4aa7b8fde56df04af6fa2025-08-20T02:38:18ZengWileyHemaSphere2572-92412025-06-0196n/an/a10.1002/hem3.70150Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencingSéverine Marti0Philippe Pellet1Blandine Beaupain2Léa Durix3Julien Buratti4Yves Réguerre5Nathalie Aladjidi6Saba Azarnoush7Severine Clauin8Wahid Abou Chahla9Gilles Blaison10Jeremy Bertand11Damien Bodet12Benoit Brethon13Jessica Chane‐Teng14Manon Delafoy15Chrystelle Dupraz16Virginie Gandemer17Philippe Denizeau18Alice Goldenberg19Pierre Hirsch20Anaïs l'Haridon21Aude Marie‐Cardine22Gabriella Vera23Brigitte Nelken24Laure Nizery25Marie Nolla26Marlène Pasquet27Jérémie Rosain28Louis Terriou29Isabelle Plo30Jean Donadieu31Christine Bellanné‐Chantelot32Department of Medical Genetics, Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (AP‐HP) Sorbonne University Paris FranceDepartment of Medical Genetics, Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (AP‐HP) Sorbonne University Paris FranceFrench Registry of Chronic Neutropenia Trousseau Hospital Paris FranceINSERM UMR1287, Gustave Roussy Paris‐Saclay University Villejuif FranceDepartment of Medical Genetics, Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (AP‐HP) Sorbonne University Paris FranceDepartment of Pediatric Oncology and Hematology Centre Hospitalo‐Universitaire (CHU) de Saint Denis La Réunion FranceDepartment of Pediatric Oncology and Hematology CHU Bordeaux Bordeaux FranceDepartment of Pediatric Hematology and Immunology Robert Debré Hospital, AP‐HP Paris FranceDepartment of Medical Genetics, Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (AP‐HP) Sorbonne University Paris FranceDepartment of Pediatric Hematology CHU Lille Lille FranceDepartment of Internal Medicine Louis Pasteur Hospital Colmar FranceLaboratoire SeqOIA (FMG2025) Paris FranceDepartment of Pediatric Hematology and Oncology CHU de Caen Caen FranceDepartment of Pediatric Hematology and Immunology Robert Debré Hospital, AP‐HP Paris FranceSorbonne University, INSERM UMRS 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP‐HP Paris FranceFrench Registry of Chronic Neutropenia Trousseau Hospital Paris FranceDepartment of Pediatric Hematology and Oncology CHU Poitiers Poitiers FranceDepartment of Pediatric Hematology and Oncology CHU Hôpital Sud Rennes FranceDepartment of Medical Genetics CHU Rennes Rennes FranceDepartment of Medical Genetics CHU Rouen Rouen FranceDepartment of Biological Hematology, Saint‐Antoine Hospital, INSERM, Centre de Recherche Saint‐Antoine, CRSA, AP‐HP, SIRIC CURAMUS Sorbonne University Paris FranceLaboratoire SeqOIA (FMG2025) Paris FranceDepartment of Pediatric Hematology and Oncology Rouen University Hospital Rouen FranceDepartment of Medical Genetics CHU Rouen Rouen FranceDepartment of Pediatric Hematology CHU Lille Lille FrancePediatric Department Delafontaine Hospital Saint‐Denis FranceDepartment of Pediatric Hematology and Oncology CHU Toulouse Toulouse FranceDepartment of Pediatric Hematology and Oncology CHU Toulouse Toulouse FranceCentre d'étude des Déficits Immunitaires, Necker Hospital, AP‐HP Paris FranceDepartment of Internal Medicine and Hematology CHU Lille Lille FranceINSERM UMR1287, Gustave Roussy Paris‐Saclay University Villejuif FranceFrench Registry of Chronic Neutropenia Trousseau Hospital Paris FranceDepartment of Medical Genetics, Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (AP‐HP) Sorbonne University Paris FranceAbstract Congenital neutropenia (CN) comprises a heterogeneous group of rare genetic disorders. While some CN cases present only with neutropenia, others present with additional extra‐hematological manifestations. The most common cause of CN is variants in ELANE; however, approximately 30 other genes have been implicated. Despite this, the genetic basis remains unknown in roughly 30% of cases. The clinical and genetic heterogeneity of CN makes diagnosis particularly challenging. To address this, we conducted exome or genome sequencing of 60 patients with a suspected diagnosis of CN that remained unresolved following targeted sequencing. A genetic diagnosis was established in 25 patients (42%). Variants were identified in 15 different genes. Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (GINS4, CARD11, ADA2, GINS1, LCP1, SASH3, and WAS). One‐third of the cases carried variants in genes linked to syndromic disorders (VPS13B, TAFAZZIN, CLPB, and TONSL), demonstrating variable penetrance of extra‐hematological phenotypes. A smaller subset (15%) harbored variants in genes associated with inherited bone marrow failure syndromes (BLM, RPL18, SAMD9, and SRP72), identified incidentally due to atypical presentations. Compared to patients with ELANE‐CN, these individuals were diagnosed later, had fewer severe bacterial infections and gingivitis, exhibited less profound neutropenia, lacked monocytosis, and had a granulocytic maturation arrest, often beyond the promyelocytic stage. A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells. This study highlights the significant contribution of exome and genome sequencing in diagnosing CN, given the phenotypic overlap, genetic heterogeneity, and variable penetrance of immunological and extra‐hematological features.https://doi.org/10.1002/hem3.70150 |
| spellingShingle | Séverine Marti Philippe Pellet Blandine Beaupain Léa Durix Julien Buratti Yves Réguerre Nathalie Aladjidi Saba Azarnoush Severine Clauin Wahid Abou Chahla Gilles Blaison Jeremy Bertand Damien Bodet Benoit Brethon Jessica Chane‐Teng Manon Delafoy Chrystelle Dupraz Virginie Gandemer Philippe Denizeau Alice Goldenberg Pierre Hirsch Anaïs l'Haridon Aude Marie‐Cardine Gabriella Vera Brigitte Nelken Laure Nizery Marie Nolla Marlène Pasquet Jérémie Rosain Louis Terriou Isabelle Plo Jean Donadieu Christine Bellanné‐Chantelot Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing HemaSphere |
| title | Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing |
| title_full | Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing |
| title_fullStr | Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing |
| title_full_unstemmed | Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing |
| title_short | Expanding the phenotypic and genetic landscape of congenital neutropenia through whole‐exome and genome sequencing |
| title_sort | expanding the phenotypic and genetic landscape of congenital neutropenia through whole exome and genome sequencing |
| url | https://doi.org/10.1002/hem3.70150 |
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